Substituted- dihydrobenzothia-
diazines



United States Patent 9 Claims. (Cl. 260--243) This application is a 'continuation-in-part of our copending prior application Serial No. 812,097, filed May 11, 1959, for Substituted Dihydrobenzothiadiazines, and since abandoned, and its companion prior application Serial No. 812,096, filed May 11, 1959, for Substituted Dihydrobenzothiadiazines, likewise a copending applica tion by us and likewise since abandoned, which the firstmentioned prior application as filed referred to for its method of making the starting material.

There are now copending two United States applica tions by us claiming 6-trifluoromethyl-7-sulfamyl-3,4-di hydro-1,2,4-benzothiadiazine-l,l-dioxide compounds of a non-spiro nature, and any claims involving non-spiro subject matter will be found in one of them, rather than this present application:

(1) Our now copending US. application Serial No. 831,949, filed August 6, 1959, for Substituted Dihydrobenzothiadiazines has as its subject matter such compounds having an aromatically substituted aliphatic radical in the 3-position and the alkali metal salts thereof and claims relating to that subject matter will be found therein.

(2) Our now copending US. application Serial No. 3,985, filed January 22, 1960, for 6-Trifluoromethyl-7- Sulfamyl 3,4 Dihydro-1,2,4 Benzothiadiazine-1,l-Dioxides and Salts Thereof, has as its subject matter the unsubstituted such compound and certain other non-spiro such compounds which have certain 3-substitutions of other things than aromatically substituted aliphatic radicals, together with their alkali metal salts, and claims relating to that subject matter will be found therein. This last application 3,985 may well turn out to have become a patent by the time this present application becomes onef This invention relates to certain novel 7-sulfamyl-3,4- dihydro 1,2,4 benzothiadiazine-1,1-dioxides, and proc esses of preparing the same.

The invention more particularly relates to compounds of the general formula:

and alkali metal salts thereof, wherein R is selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro, amino, lower alkyl and lower alkoxy; R and R are selected from the group consisting of hydrogen, halogen and lower alkyl; and n is one or two. Particularly preferred are compounds wherein R is chlorine, bromine, trifluoromethyl or nitro, and R is hydrogen.

When reference is made herein to lower alkyl it is intended to include methyl, ethyl and propyl, and when reference is made to lower alkoxy it is intended to include methoxy, ethoxy and propoxy. Thus there are one to three carbon atoms inclusive in lower alkyl and lower alkoxy.

3,254,077 Patented May 31, 1966 It should be recognized that there are alternate nomenclatures which are used for the compounds under discussion. Thus cyclohexane 1',3 spiro-6-chloro-7-sulfamyl- 3,4-dihydro 1,2,4 benzothiadiazine-l,l-dioxide may be written as spiro-['6-chloro-7-sulfamyl-3,4-dihydro-1,2,4- benzothiadiazine- 1 1-dioxide-3 ,1'-cyclohexane] Similarly 2'-chloro-cyclohexane l,3-spiro-6-chloro-7-sulfamyl- 3,4-dihydro 1,2,4 benzothiadiazine-l,l-dioxide may be written as spiro-[6-chloro-7-sulfamyl-3,4-dihydro-1,2,4- benzothiadiazine 1,1 dioxide-3,1'(2'-chloro-cyclohexane)].

The new 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxides of this invention are physiologically active compounds which exert strongly saluretic and diuretic effects. Thus the compounds of this invention are administerable parenterally externally andpreferably orally in the treatment of conditions requiring diuretic agents. This effect is obtained on animals, including lower animals and humans.

The compounds of this invention can be prepared by reacting a 2,4-disulfamylaniline of the general formula:

wherein n and R are as hereinbefore defined, or a reactive derivative thereof, as more fully described hereinafter, thereby yielding the compounds of this invention.

The 2,4-disulfamyl-aniline reactant can be prepared by reacting an aniline with chlorosulfonic acid and treating the resulting aniline-2,4-disulfonyl chloride with ammonia, in a manner analogous to that described in the specification to US. Patent No. 2,809,194.

Among suitable initial aniline reactants may be mentioned: 2-haloanilines, such as 2-chloroand 2-bromoanilines; 3-haloanilines, such as 3-chloroand 3-bromoaniline; B-trifiuoromethylaniline; 2,3-dihaloanilines, such as 2,3-dichloroaniline; 2-lower alkylanilines, such as o-toluidine and 2-ethyl-aniline; 3-lower alkylanilines, such as m-toluidine, 3-ethyl-aniline, and 3-n-butylaniline; 2-halo-3-lower alkylanilines, such as 2-chloro-3- methylaniline; 2 lower alkyl 3 haloanilines, such as 2-methyl-3-chloroaniline; 3-nitroaniline; 2-halo-3-nitroanilines, such as Z-chloro-Z-nitroaniline; 3-lower alkoxyanilines, such as m-anisidine; and 2-(lower alkyl)-3-nitroanilines, such as 2-methyl-3-nitroaniline.

The reactive derivatives of the compounds of Formula III include ketals of these compounds, particularly di- (lower alkyl)-ketals. anilinewith the compound of Formula III is preferably conducted in the presence of an acid catalyst, such as hydrochloric, phosphoric, p-toluenesulfonic, trichloroacetic or sulfuric acid.

If an alkali metal salt is desired, it can be formed by reacting the free 7-sulfamyl-3,4-dihydro-1,2,4 benzothiadiazine-1,1-di0xide with an alcoholic solution of the alkali metal hydroxide in question (e.g. potassium hydroxide), as described in US. Patent No. 2,809,194.

(III) I The reaction of the 2,4-disulfamyl- EXAMPLE 1 Preparation of starting materials (a) Preparation of 5-trifluoromethylaniline-2,4-disalfonyl chloride.l13 ml. of chlorosulfonic acid was cooled in an ice-bath, and to the acid was added dropwise while stirring 26.6 -g. of a,a,u-trifluoro-mdoluidine. 105 g. of sodium chloride was added during 1-2 hours, whereafter the temperature of the reaction mixture was raised slowly to 150-160, which temperature was maintained for three hours. After cooling the mixture, icecooled water was added, whereby S-trifluoromethylaniline-2,4-disulfonyl chloride separated out from the mixture.

(b) Preparation of S-trifluoromethyl-Z,4-disulfamylaniline.The 5-trifluoromethylaniline-2,4-disulfonyl chloride obtained in step (a) was taken up in ether and the ether solution dried with magnesium sulfate. The ether was removed from the solution by distillation, the residue was cooled to C., and 60 ml. of ice-cooled, concentrated ammonia water was added while stirring. The solution was then heated for one hour on a steam bath and evaporated in vacuo to crystallization. The crystallized product was S-trifluoromethyl-2,4-disulfamylaniline, which was filtered off, washed with water and dried in a vacuum exsiccator over phosphorus pentoxide. After recrystallization from a mixture of 30% ethanol and 70% water the compound had a M.P. of 247-248".

The following examples illustrate the invention (all temperatures being in centigrade);

EXAMPLE 2 Cyclopentane-I ,3-spiro-6-trifluoromethyl 7 sulfamyl- 3,4-dihydr0-1,2,4-benz0thiadiazine-1,1-di0xide.-3.2 g. of -trifluorornethyl-2,4-disulfamylaniline produced as in Example 1 and a few crystals of p-toluenesulfonic acid were dissolved in 20 ml. of cyclopentanone, and the mixture was boiled with reflux for 24 hours. After cooling, the reaction mixture was poured into 150 ml. of petroleum ether (boiling range 105120). The oily substance which separated out crystallized after stirring for a while. The crystals were separated from the solution and washed with petroleum ether. Thereby 3.7 g. of the reaction product was obtained with a M.P. of 200-210 (decomposition). The dark colored crystalline product was purified by suspension in ml. of ethanol and filtering off the undissolved substance, which was subsequently recrystallized from ml. of ethanol. Thereby the desired reaction product was obtained with a M.P. of 232.5- 234.

EXAMPLE 3 Dipotassium salt of cyclopentane-I,3-spir0-6-trifluor0- methyl-7-sulfamyl-3,4-dihydro 1,2,4 benzothiadiazine- 1,1-di0xide.To a solution of 6.6 g. of 85% potassium hydroxide in 100 ml. of 95% ethanol was added gradually with shaking 19.2 g. of cyclopentane-1',3-spiro-6- trifluoromethyl-7-sulfamyl 3,4 dihydro-1,2,4-benzothiadiazine-1,1-dioxide. The solid dissolved. The resulting alcoholic solution was concentratedin vacuo to yield the dipotassium salt as a free-flowing granular powder.

Similarly, using the equivalent quantity of sodium hydroxide instead of potassium hydroxide, the disodium salt was obtained. Furthermore, if only 3.3 g. of 85% potassium hydroxide was used in Example 3, the monopotassium salt was obtained.

EXAMPLE 4 Cyclohexane-l,3-spir0-6-triflu0r0methyl 7-sulfamyl- 3,4-dihydro-1,2,4-benzothiadiazine-I,1-di0xide.-3.2 g. of 5-trifluoromethyl2,4-disulfamylaniline was dissolved in 20 ml. of cyclohexanone, a catalytic amount of p-toluenesulfonic acid was added, and the solution was boiled with reflux overnight. After cooling, the reaction mixture was poured into 150 m1. of petroleum ether (boiling range IDS-120). The oily substance, which separated out, crystallized after stirring for a while. The crystals were separated from the solution, washed with petroleum ether (boiling range -40) and, after drying, recrystallized from ethanol. The recrystallized product had a M.P. of 261-262 0.

EXAMPLE 5 EXAMPLES 6-11 Following the procedure of Example 4, but substituting the required 5,6-substituted-2,4-disulfamylaniline for the 5-trifluoromethyl-2,4-disulfamylaniline, the following cyclohexane 1',3 spiro-5-Y-6-Z-7 sulfamy1-3,4-dihydro- 1,2,4-benzothiadiazine-1,1-clioxide derivatives were obtained.

M.P. Recrystallized from- Ethanol/hexane. 2-ethoxyethanol/hexane. Dimethylformamide/water. Formamide/water. Acetone/hexane. Dimethylformamide/water.

EXAMPLE 12 Cyclohexane ,3 spiro 6 amin0-7-sulfamyl-3,4- dihydro-J,2,4-benz0thiadiazine 1,J-dioxzlda-A solution of 1.6 g. of cyclohexane-Z-spiro-6-nitro-7-sulfamyl-3,4- dihydro-l,2,4 benzothiadiazine-1,l-dioxide in 30 ml. of 2- methoxyethanol was hydrogenated over mg. of platinum catalyst at room temperature with hydrogen at a pressure of one atmosphere. When the theoretical amount of hydrogen had been. absorbed, 3 ml. of 2 N sodium hydroxide solution was added, and the catalyst was filtered off. The reaction product was precipitated from the filtrate by acidification with acetic acid. By recrystallization from aqueous sodium hydroxide/acetic acid, colorless crystals of the desired substance were obtained.

- EXAMPLE 13 2' methylcyclohexane 1',3 spiro 6 trifluoromethyl- 7 sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine 1,1 -dioxide.Following the procedure of Example 4, but substituting Z-methylcyclohexanone for the cyclohexanone, the 2 methylcyclohexane-1',3-spiro-6-trifluoromethyl 7 sulfamyl-3,4-dihydro-1,2,4-benzoth-iadiazine- 1,1-dioxide was obtained. After recrystallization from methanol the desired substance was obtained in pure state with a M.P. of 232-234.

EXAMPLE 14 Cyclopentane 1',3 spiro 6 chloro 7 sulfamyl- 3,4 dihydro 1,2,4 benzothiadiazine 1,1 dioxide. 4 g. of 5-chloro-2,4-disulfamylaniline was 'dissolved in 35 m1. of cyclopentanone. .A catalytic amount of ptoluenesulfonic acid was added, and the mixture was boiled with reflux for 6 hours. After cooling, a mixture of methylene chloride and hexane was added, whereby the reaction product precipitated out. The precipitate was dissolved in hot dioxane and after cooling precipitated by addition of a mixture of methylene chloride and hexane. By recrystallization from 99% ethanol the de; sired substance was obtained with a M.P. of 234.

EXAMPLE 2' m'ethylcyclohexane 1'3 spiro 6 -br0m0 7- sulfamyl 3,4-dihydro 1,2,4 benzothiaa'iazine 1,1- di0xide.-4 g. of 5bromo-2,4-disulfamylaniline was dissolved in ml. of Z-methyl-cyclohexanone. A catalytic amount of p-toluenesulfonic acid was added, and the mixture was boiled with reflux overnight. After cooling, the unreacted 5-bromo-2,4-disulfamylaniline was filtered off, and to the filtrate hexane was added until the reaction product was precipitated out. The precipitate was dissolved in n-propanol and reprecipitated by' addition of a mixture of methylene chloride and hexane. By recrystallization from methanol/water the desired substance 'was obtained with a M.P. of 231-233 EXAMPLE 16 2' chlorocyclohexane 1',3 spiro 6 trifluoromethyl- 7 sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine 1,1 di0xide.-6.4. g. of S-trifluoromethyl-2,4-disulfamylaniline and 4.6 g. of l,1-diethoxy-2-chlorocyclohexane were dissolved in 20 ml. of dioxane. A catalytic amount of ptoluenesulfonic acid was added, and the mixture was boiled with reflux for 24 hours. After cooling, the reaction mixture was poured into 200 ml. of hexane, and the precipitate thereby formed was recrystallized twice from methanol/water. The desired substance was thereby obtained with a MP. of 218-219" (decomposition).

EXAMPLE 17 2 chlorocyclohexane 1',3 spiro 6 chloro 7- sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine 1,1- dioxide.5.8 g. of 5-chloro-2,4-disulfamylaniline and 4.6 g. of i-chloro-2-diethoxy cyclohexane were dissolved in 50 ml. of dioxane. A catalytic amount of p-toluenesulfonic acid was added, and the mixture was boiled with reflux overnight. After cooling, the reaction mixture was precipitated by addition of hexane. The precipitate was dissolved in methanol, and by addition of water the desired substance crystallized out, and by recrystallization from dimethylformamide/ water it was obtained with a MP. of 223-225 EXAMPLE 18 4' chlorocyclohexane 1,3 spiro 6 trifluoromethyb 7 sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine 1,1- di0xide.6.4 g. of S-trifluoromethyl-2,4-disulfamylaniline and 2.9 g. of 4-chlorocyclohexanone were dissolved in 20 ml. of dioxane. A catalytic amount of p-toluenesulfonic acid was added, and the mixture was boiled with reflux for 20 hours. After cooling, the reaction mixture was poured into 300 ml. of hexane. The precipitate thereby formed was recrystallized from methanol/water. Thereby the desired substance was obtained with a MP. of

217218 (decomposition).

EXAMPLE 19 4' chlorocyclohexane 1',3 spiro 6 chloro 7- sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine 1,1- di0xide.5.8 g. of 5-chloro-2,4-disulfamylaniline and 2.9 g. of 4-chloro-cyclohexanone were dissolved in 50 ml. of diethylene glycol dimethyl ether. A catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated to 125 overnight. After cooling, the reaction product was precipitated by addition of hexane. The precipitate was dissolved in methanol and reprecipitated by addition of amixture of methylene chloride and hexane. By recrystallization from methanol/Water the desired substance was obtained with a MP. of 2195-2205".

In a series of tests with rats the saluretic effects of the compounds of this invention were compared with the saluretic effects of the widely used diuretic agent 6- chloro 7 sulfamyl 1,2,4 benzothiadiazine-1,1-dioxide (chlorothiazide). Three animals each received a single oral dose of a solution of the indicated test substance. The amounts of urine were measured, and the contents 6 of sodium, potassium and chloride ions were determined six hours after administering the test substance. From these figures average values for the total excretions of the said three ions during six hours were calculated in micro-equivalents per group of three animals. The results of these tests are shown in the following table, in which the figures in column 1 are the numbers of the examples:

Excretions in micro- Iest Substance Dose, equivalents ofmg./kg

Na+ K+ Cl- In view of our invention and disclosure, variations and modifications to meet individual wh-im or particular need will doubtless become evident to others skilled in the art, to obtain all or part of the benefits of our invention without copying the compound and process shown, and we, therefore, claim all such insofar as they fall within the reasonable spirit and scope of our claims.

In view of our invention and disclosure what we claim as new and desire to secure by Letters Patent is:

1. A compound selected from the group of dihydrobenzothiadiazines of the general formula and alkali metal salts thereof, wherein R is selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro, amino, lower alkyl, and lower alkoxy; R and R are selected from the group consisting of hydrogen, halogen and lower alkyl; and n is selected from the group consisting of one and two.

2. Cyclohexane 1',3 spiro 6 chloro 7 sulfamyl- 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

3. cyclohexane 1',3 spiro 6 bromo 7 sulfamyl- 3,4-dihydro-1,2,4 benzothiadiazine-1,1-d-ioxide.

4. Cyclohexane l',3 spiro 6 lower alkyl-7-sulfamyl- 3,4-dihydro-1,2,4- benZothiadiaZine-l,l-dioxide.

8. A compound of the formula HaNOzS ing of the chloro and t-rifluoromethyl radicals.

9. A compound selected from the group consisting of compounds of the formula HzNOzS CH3C H:

and the alkali metal salts thereof, wherein n is a number selected from the group consisting of'one and two.

i References Cited by the Examiner Chem. Abstracts, vol. 39, page 5885 (1945).

Holdrege et al.: Journ. American Chem. Soc., vol. 81, pages 4807-11 (1959).

Merck: Australian Abstract 43, 757/58, Open to Public Inspection, May 28, 1959.

Patterson-Capell: The Ring Index (1940), pages 26.27, A.C.S. Monograph Series No. 84, Reinhold Pub. Corp. N.W.

NICHOLAS s. RIZZO, Primary Examiner.-

IRVING MARCUS, Examiner.

G. S. ROSEN, Assistant Examiner. 

1. A COMPOUND SELECTED FROMTHE GROUP OF DIHYDROBENZOTHIADIAZINES OF THE GENERAL FORMULA 